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Mante N, Undale V, Sanap A, Bhonde R, Tambe P, Bansode M, Gupta RK. Disease microenvironment preconditioning: An evolving approach to improve therapeutic efficacy of human mesenchymal stromal cells. Int Immunopharmacol 2025; 157:114701. [PMID: 40300358 DOI: 10.1016/j.intimp.2025.114701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/10/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025]
Abstract
Despite the tremendous success in preclinical models, the translation of human mesenchymal stromal cells (hMSCs) as a therapy in the clinic is not up to the expectation. Intrinsic factors (age, sex, health status, life style of the donor, source, cellular senescence, and oxidative stress in hMSCs), extrinsic factors (culture system, batch-to-batch variations, choice of biomaterials, cell processing and preservation protocols), and host microenvironment (inflammatory milieu, oxidative stress, and hypoxia in the recipient) compromise the overall therapeutic efficacy of the transplanted hMSCs. In recent times, the approach of 'Disease Microenvironment Preconditioning (DMP)' has garnered attention to overcome the host-associated attributes involved in compromised hMSCs therapeutic potential. In this review, we discuss various approaches of DMP of hMSCs by employing serum and other body fluids obtained from diseased patients/animals and small molecules, including cytokines such as IFN-γ, IL-6, IL-10, IL- β, TGF-β1, IL-1α, IL-1β, TNF-α, HMGB1, IL-17 A, and IL-8 which are associated with disease conditions. DMP strengthens hMSCs ability to adapt/acclimatize and respond more efficiently to the hostile microenvironment they encounter upon transplantation. DMP modulate hMSCs to withstand inflammation, survive under hypoxic and nutrient-deprived conditions, and resist oxidative stress. Evidence from various disease models ranging from cardiovascular and neurodegenerative disorders to autoimmune diseases and tissue injuries supports the role of DMP in improving hMSC survival, integration, and functional efficacy. While the potential of DMP to revolutionize MSC-based therapies is evident, challenges such as standardizing/optimizing protocols for preconditioning is essential. This review synthesizes current advancements in the approach of DMP aiming to propel the area of regenerative medicine.
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Affiliation(s)
- Nishant Mante
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India
| | - Vaishali Undale
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India.
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India.
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India
| | - Pratima Tambe
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India
| | - Manoj Bansode
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Rajesh Kumar Gupta
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
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Ding Y, Yao S, Guo S, Meng W, Li J, Wang F, Zhang J, Chang YZ, Gao G. Ferroportin 1 depletion in neural stem cells promotes hippocampal neurogenesis and cognitive function in mice. Pharmacol Res 2025; 216:107778. [PMID: 40374054 DOI: 10.1016/j.phrs.2025.107778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 05/10/2025] [Accepted: 05/11/2025] [Indexed: 05/17/2025]
Abstract
In the adult brain, newborn granule cells continuously integrate into the hippocampal circuits, and fine-tuning the regulation of this process is crucial for improving hippocampal function. Iron is an essential element for the development and functionality of the brain. Ferroportin 1 (Fpn1) is an iron efflux transporter that plays a crucial role in regulating cellular iron release. In this study, Nestin-CreERT2-mediated Fpn1 conditional knockout (cKO) mice were established to investigate the impact of Fpn1 depletion in neural stem cells (NSCs) on adult hippocampal neurogenesis. Interestingly, we found that the cKO mice presented better learning and memory abilities and fewer anxiety-like behaviors. The numbers of self-renewing NSCs and NSCs undergoing proliferation and differentiation were significantly increased in the hippocampus of Fpn1 cKO mice, resulting in greater numbers of newborn neurons than in control mice. Further investigation revealed that the elevated iron levels in NSCs and iron-mediated increase in ROS generation in Fpn1 cKO mice contributed to the enhanced hippocampal neurogenesis through PI3K/Akt and MAPK signaling activation. Notably, iron supplementation promoted the proliferation of primary NSCs dose-dependently, whereas the presence of ROS inhibitor abolished this effect. This study reveals that Fpn1 of NSCs and its regulated iron levels are key modulators of hippocampal neurogenesis through promoting the proliferation of NSCs and ultimately controlling hippocampal function. These findings may provide valuable insights into stem cell-targeting treatments for neurological diseases.
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Affiliation(s)
- Yiqian Ding
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
| | - Shanshan Yao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
| | - Shuxin Guo
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
| | - Wei Meng
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
| | - Jie Li
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jianhua Zhang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China..
| | - Yan-Zhong Chang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China..
| | - Guofen Gao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Collaborative Innovation Center for Eco-Environment; Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China..
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Warren AJ, Liu L, O'Toole DP, Laffey JG, Masterson CH. The impact of the inflammatory pulmonary microenvironment on the behavior and function of mesenchymal stromal cells. Expert Rev Respir Med 2025:1-12. [PMID: 40223328 DOI: 10.1080/17476348.2025.2491715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 03/28/2025] [Accepted: 04/07/2025] [Indexed: 04/15/2025]
Abstract
INTRODUCTION Acute respiratory distress syndrome is characterized by the dysregulation and activation of several inflammatory pathways which lead to widespread inflammation in the lungs. Presently, direct therapy is unavailable and the use of mesenchymal stromal cells as a direct therapy has been proposed, as early-phase studies have shown promise. AREAS COVERED MSCs exert various therapeutic effects on the inflammatory microenvironment, such as anti-microbial effects, restoration of the alveolar-capillary barrier, and exuding various anti-inflammatory effects. However, to exert these effects MSCs need to be submitted to specific external stimuli which can affect their immunomodulation, survival, migration and metabolic state. This review references several articles found through targeted searches in PubMed [Accessed between November 2024 and March 2025], for key terms such as 'mesenchymal stromal cells', 'inflammatory microenvironment', anti-inflammatory', 'metabolism', and 'immunomodulation'. EXPERT OPINION The advancement of MSCs therapy in the treatment of ARDS has not progressed as effectively as one might have anticipated. Several clinical findings have established patient subgroups based on inflammatory cytokine profiles and severity of ARDS. This variation in patients may influence the clinical efficacy of MSCs and instead of concluding that MSCs therapy is not worth pursuing, more research is needed to develop an appropriate therapy.
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Affiliation(s)
- Abigail Jm Warren
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Lanzhi Liu
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Daniel P O'Toole
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - John G Laffey
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland
| | - Claire H Masterson
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
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Bradshaw KJ, Leipzig ND. Applications of Regenerative Tissue-Engineered Scaffolds for Treatment of Spinal Cord Injury. Tissue Eng Part A 2025; 31:108-125. [PMID: 39556330 DOI: 10.1089/ten.tea.2024.0194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024] Open
Abstract
Tissue engineering provides a path forward for emerging personalized medicine therapies as well as the ability to bring about cures for diseases or chronic injuries. Traumatic spinal cord injuries (SCIs) are an example of a chronic injury in which no cure or complete functional recovery treatment has been developed. In part, this has been due to the complex and interconnected nature of the central nervous system (CNS), the cellular makeup, its extracellular matrix (ECM), and the injury site pathophysiology. One way to combat the complex nature of an SCI has been to create functional tissue-engineered scaffolds that replace or replenish the aspects of the CNS and tissue/ECM that are damaged following the immediate injury and subsequent immune response. This can be achieved by employing the tissue-engineering triad consisting of cells, biomaterial(s), and environmental factors. Stem cells, with their innate ability to proliferate and differentiate, are a common choice for cellular therapies. Natural or synthetic biomaterials that have tunable characteristics are normally used as the scaffold base. Environmental factors can range from drugs to growth factors (GFs) or proteins, depending on if the idea would be to stimulate exogeneous or endogenous cell populations or just simply retain cells on the scaffold for effective transplantation. For functional regeneration and integration for SCI, the scaffold must promote neuroprotection and neuroplasticity. Tissue-engineering strategies have shown benefits including neuronal differentiation, axonal regeneration, axonal outgrowth, integration into the native spinal cord, and partial functional recovery. Overall, this review focuses on the background that causes SCI to be so difficult to treat, the individual components of the tissue-engineering triad, and how combinatorial scaffolds can be beneficial toward the prospects of future SCI recovery.
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Affiliation(s)
- Katherine J Bradshaw
- Department of Biomedical Engineering, Auburn Science and Engineering Center #275, The University of Akron, Akron, Ohio, USA
| | - Nic D Leipzig
- Department of Biomedical Engineering, Auburn Science and Engineering Center #275, The University of Akron, Akron, Ohio, USA
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio, USA
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Li P, Zhang W, Zhang J, Liu J, Fu J, Wei Z, Le S, Xu J, Wang L, Zhang Z. Macrophage migration inhibitory factor promotes heterotopic ossification by mediating ROS/HIF-1α positive feedback loop and activating Wnt/β-catenin signaling pathway. Bone 2025; 190:117331. [PMID: 39549900 DOI: 10.1016/j.bone.2024.117331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF. METHODS TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo. RESULTS The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway. CONCLUSION MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs.
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Affiliation(s)
- Ping Li
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Wensheng Zhang
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Jie Zhang
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Jie Liu
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Jiaming Fu
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhengnong Wei
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Shiyong Le
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China
| | - Jiajia Xu
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Liang Wang
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China.
| | - Zhongmin Zhang
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Adly HA, El-Okby AWY, Yehya AA, El-Shamy AA, Galhom RA, Hashem MA, Ahmed MF. Circumferential Esophageal Reconstruction Using a Tissue-engineered Decellularized Tunica Vaginalis Graft in a Rabbit Model. J Pediatr Surg 2024; 59:1486-1497. [PMID: 38692944 DOI: 10.1016/j.jpedsurg.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 03/26/2024] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND Pediatric surgeons have faced esophageal reconstruction challenges for decades owing to a variety of congenital and acquired conditions. This work aimed to introduce a reproducible and efficient approach for creating tissue-engineered esophageal tissue using bone marrow mesenchymal stem cells (BMSCs) cultured in preconditioned mediums seeded on a sheep decellularized tunica vaginalis (DTV) scaffold for partial reconstruction of a rabbit's esophagus. METHODS DTV was performed using SDS and Triton X-100 solutions. The decellularized grafts were employed alone (DTV group) or after recellularization with BMSCs cultured for 10 days in preconditioned mediums (RTV group) for reconstructing a 3 cm segmental defect in the cervical esophagus of rabbits (n = 20) after the decellularization process was confirmed. Rabbits were observed for one month, after which they were euthanized, and the reconstructed esophagi were harvested for histological analysis. RESULTS Six rabbits in the DTV group and eight rabbits in the RTV group survived until the end of the one-month study period. Despite histological examination demonstrating that both grafts completely repaired the esophageal defect, the RTV graft demonstrated a histological structure similar to that of the normal esophagus. The reconstructed esophagi in the RTV group revealed the arrangement of the different layers of the esophageal wall with the formation of newly formed blood vessels and Schwann-like cells. CONCLUSION DTV xenograft is a novel scaffold that promotes cell adhesion and differentiation and might be effectively utilized for regenerating esophageal tissue, paving the way for future clinical trials in pediatric patients.
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Affiliation(s)
- Hassan A Adly
- Pediatric Surgery Unit, General Surgery Department, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut, Egypt.
| | - Abdel-Wahab Y El-Okby
- Department of Pediatric Surgery, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Abdel-Aziz Yehya
- Department of Pediatric Surgery, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed A El-Shamy
- Pediatric Surgery Unit, General Surgery Department, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut, Egypt
| | - Rania A Galhom
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Tissue Culture Lab, Center of Excellence of Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Human Anatomy and Embryology, Faculty of Medicine, Badr University in Cairo (BUC), Cairo, Egypt
| | - Mohamed A Hashem
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Mahmoud F Ahmed
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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Dogny C, André-Lévigne D, Kalbermatten DF, Madduri S. Therapeutic Potential and Challenges of Mesenchymal Stem Cell-Derived Exosomes for Peripheral Nerve Regeneration: A Systematic Review. Int J Mol Sci 2024; 25:6489. [PMID: 38928194 PMCID: PMC11203969 DOI: 10.3390/ijms25126489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context, mesenchymal stem cell (MSC)-derived exosomes have emerged as a potential therapeutic option. Thus, the focus of this study was to review currently available data on MSC-derived exosome-mounted scaffolds in peripheral nerve regeneration in order to identify the most promising scaffolds and exosome sources currently in the field of peripheral nerve regeneration. We conducted a systematic review following PRISMA 2020 guidelines. Exosome origins varied (adipose-derived MSCs, bone marrow MSCs, gingival MSC, induced pluripotent stem cells and a purified exosome product) similarly to the materials (Matrigel, alginate and silicone, acellular nerve graft [ANG], chitosan, chitin, hydrogel and fibrin glue). The compound muscle action potential (CMAP), sciatic functional index (SFI), gastrocnemius wet weight and histological analyses were used as main outcome measures. Overall, exosome-mounted scaffolds showed better regeneration than scaffolds alone. Functionally, both exosome-enriched chitin and ANG showed a significant improvement over time in the sciatica functional index, CMAP and wet weight. The best histological outcomes were found in the exosome-enriched ANG scaffold with a high increase in the axonal diameter and muscle cross-section area. Further studies are needed to confirm the efficacy of exosome-mounted scaffolds in peripheral nerve regeneration.
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Affiliation(s)
- Clelia Dogny
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Dominik André-Lévigne
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Daniel F. Kalbermatten
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
- Bioengineering and Neuroregeneration Laboratory, Department of Surgery, University of Geneva, 1211 Geneva, Switzerland
| | - Srinivas Madduri
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
- Bioengineering and Neuroregeneration Laboratory, Department of Surgery, University of Geneva, 1211 Geneva, Switzerland
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Olatunji G, Kokori E, Yusuf I, Ayanleke E, Damilare O, Afolabi S, Adetunji B, Mohammed S, Akinmoju O, Aboderin G, Aderinto N. Stem cell-based therapies for heart failure management: a narrative review of current evidence and future perspectives. Heart Fail Rev 2024; 29:573-598. [PMID: 37733137 DOI: 10.1007/s10741-023-10351-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2023] [Indexed: 09/22/2023]
Abstract
Heart failure (HF) is a prevalent and debilitating global cardiovascular condition affecting around 64 million individuals, placing significant strain on healthcare systems and diminishing patients' quality of life. The escalating prevalence of HF underscores the urgent need for innovative therapeutic approaches that target the root causes and aim to restore normal cardiac function. Stem cell-based therapies have emerged as promising candidates, representing a fundamental departure from conventional treatments focused primarily on symptom management. This review explores the evolving landscape of stem cell-based therapies for HF management. It delves into the mechanisms of action, clinical evidence from both positive and negative outcomes, ethical considerations, and regulatory challenges. Key findings include the potential for improved cardiac function, enhanced quality of life, and long-term benefits associated with stem cell therapies. However, adverse events and patient vulnerabilities necessitate stringent safety assessments. Future directions in stem cell-based HF therapies include enhancing efficacy and safety through optimized stem cell types, delivery techniques, dosing strategies, and long-term safety assessments. Personalized medicine, combining therapies, addressing ethical and regulatory challenges, and expanding access while reducing costs are crucial aspects of the evolving landscape.
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Affiliation(s)
- Gbolahan Olatunji
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Kokori
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Ismaila Yusuf
- Department of Medicine and Surgery, Obafemi Awolowo University, Osun, Nigeria
| | - Emmanuel Ayanleke
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Olakanmi Damilare
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Samson Afolabi
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Busayo Adetunji
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Saad Mohammed
- Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
| | | | - Gbolahan Aboderin
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Nicholas Aderinto
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria.
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Li DY, Li YM, Lv DY, Deng T, Zeng X, You L, Pang QY, Li Y, Zhu BM. Enhanced interaction between genome-edited mesenchymal stem cells and platelets improves wound healing in mice. J Tissue Eng 2024; 15:20417314241268917. [PMID: 39329066 PMCID: PMC11425747 DOI: 10.1177/20417314241268917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/26/2024] [Indexed: 09/28/2024] Open
Abstract
Impaired wound healing poses a significant burden on the healthcare system and patients. Stem cell therapy has demonstrated promising potential in the treatment of wounds. However, its clinical application is hindered by the low efficiency of cell homing. In this study, we successfully integrated P-selectin glycoprotein ligand-1 (PSGL-1) into the genome of human adipose-derived mesenchymal stem cells (ADSCs) using a Cas9-AAV6-based genome editing tool platform. Our findings revealed that PSGL-1 knock-in enhanced the binding of ADSCs to platelets and their adhesion to the injured site. Moreover, the intravenous infusion of PSGL-1 -engineered ADSCs (KI-ADSCs) significantly improved the homing efficiency and residence rate at the site of skin lesions in mice. Mechanistically, PSGL-1 knock-in promotes the release of some therapeutic cytokines by activating the canonical WNT/β-catenin signaling pathway and accelerates the healing of wounds by promoting angiogenesis, re-epithelialization, and granulation tissue formation at the wound site. This study provides a novel strategy to simultaneously address the problem of poor migration and adhesion of mesenchymal stem cells (MSCs).
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Affiliation(s)
- De-Yong Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu-Meng Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dan-Yi Lv
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tian Deng
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xin Zeng
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lu You
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiu-Yu Pang
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Li
- Core Facilities of West China Hospital, Sichuan University, Chengdu, China
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Santos RT, de Sá Freire Onofre ME, de Assis Fernandes Caldeira D, Klein AB, Rocco PRM, Cruz FF, Silva PL. Pharmacological Agents and Potential New Therapies in Pulmonary Arterial Hypertension. Curr Vasc Pharmacol 2024; 22:155-170. [PMID: 38115617 DOI: 10.2174/0115701611266576231211045731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 10/09/2023] [Accepted: 11/15/2023] [Indexed: 12/21/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.
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Affiliation(s)
- Renata Trabach Santos
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Eduarda de Sá Freire Onofre
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Dayene de Assis Fernandes Caldeira
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriane Bello Klein
- Laboratory of Cardiovascular Physiology and Reactive Oxygen Species, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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11
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Allcock B, Wei W, Goncalves K, Hoyle H, Robert A, Quelch-Cliffe R, Hayward A, Cooper J, Przyborski S. Impact of the Physical Cellular Microenvironment on the Structure and Function of a Model Hepatocyte Cell Line for Drug Toxicity Applications. Cells 2023; 12:2408. [PMID: 37830622 PMCID: PMC10572302 DOI: 10.3390/cells12192408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/26/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023] Open
Abstract
It is widely recognised that cells respond to their microenvironment, which has implications for cell culture practices. Growth cues provided by 2D cell culture substrates are far removed from native 3D tissue structure in vivo. Geometry is one of many factors that differs between in vitro culture and in vivo cellular environments. Cultured cells are far removed from their native counterparts and lose some of their predictive capability and reliability. In this study, we examine the cellular processes that occur when a cell is cultured on 2D or 3D surfaces for a short period of 8 days prior to its use in functional assays, which we term: "priming". We follow the process of mechanotransduction from cytoskeletal alterations, to changes to nuclear structure, leading to alterations in gene expression, protein expression and improved functional capabilities. In this study, we utilise HepG2 cells as a hepatocyte model cell line, due to their robustness for drug toxicity screening. Here, we demonstrate enhanced functionality and improved drug toxicity profiles that better reflect the in vivo clinical response. However, findings more broadly reflect in vitro cell culture practises across many areas of cell biology, demonstrating the fundamental impact of mechanotransduction in bioengineering and cell biology.
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Affiliation(s)
- Benjamin Allcock
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Wenbin Wei
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Kirsty Goncalves
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Henry Hoyle
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Alisha Robert
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Rebecca Quelch-Cliffe
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Adam Hayward
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
| | - Jim Cooper
- European Collection of Authenticated Cell Cultures, Salisbury SP4 0JG, UK
| | - Stefan Przyborski
- Department of Biosciences, Durham University, Durham DH1 3LE, UK; (B.A.); (W.W.); (K.G.)
- Reprocell Europe Ltd., Glasgow G20 0XA, UK
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12
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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13
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Liu T, Zhang Q, Li H, Cui X, Qi Z, Yang X. An injectable, self-healing, electroconductive hydrogel loaded with neural stem cells and donepezil for enhancing local therapy effect of spinal cord injury. J Biol Eng 2023; 17:48. [PMID: 37488558 PMCID: PMC10367392 DOI: 10.1186/s13036-023-00368-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a serious injury with high mortality and disability rates, and there is no effective treatment at present. It has been reported that some treatments, such as drug intervention and stem cell transplantation have positive effects in promoting neurological recovery. Although those treatments are effective for nerve regeneration, many drawbacks, such as low stem cell survival rates and side effects caused by systemic medication, have limited their development. In recent years, injectable hydrogel materials have been widely used in tissue engineering due to their good biocompatibility, biodegradability, controllable properties, and low invasiveness. The treatment strategy of injectable hydrogels combined with stem cells or drugs has made some progress in SCI repair, showing the potential to overcome the drawbacks of traditional drugs and stem cell therapy. METHODS In this study, a novel injectable electroactive hydrogel (NGP) based on sodium hyaluronate oxide (SAO) and polyaniline-grafted gelatine (NH2-Gel-PANI) was developed as a material in which to load neural stem cells (NSCs) and donepezil (DPL) to facilitate nerve regeneration after SCI. To evaluate the potential of the prepared NGP hydrogel in SCI repair applications, the surface morphology, self-repairing properties, electrical conductivity and cytocompatibility of the resulting hydrogel were analysed. Meanwhile, we evaluated the neural repair ability of NGP hydrogels loaded with DPL and NSCs using a rat model of spinal cord injury. RESULTS The NGP hydrogel has a suitable pore size, good biocompatibility, excellent conductivity, and injectable and self-repairing properties, and its degradation rate matches the repair cycle of spinal cord injury. In addition, DPL could be released continuously and slowly from the NGP hydrogel; thus, the NGP hydrogel could serve as an excellent carrier for drugs and cells. The results of in vitro cell experiments showed that the NGP hydrogel had good cytocompatibility and could significantly promote the neuronal differentiation and axon growth of NSCs, and loading the hydrogel with DPL could significantly enhance this effect. More importantly, the NGP hydrogel loaded with DPL showed a significant inhibitory effect on astrocytic differentiation of NSCs in vitro. Animal experiments showed that the combination of NGP hydrogel, DPL, and NSCs had the best therapeutic effect on the recovery of motor function and nerve conduction function in rats. NGP hydrogel loaded with NSCs and DPL not only significantly increased the myelin sheath area, number of new neurons and axon area but also minimized the area of the cystic cavity and glial scar and promoted neural circuit reconstruction. CONCLUSIONS The DPL- and NSC-laden electroactive hydrogel developed in this study is an ideal biomaterial for the treatment of traumatic spinal cord injury.
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Affiliation(s)
- Tiemei Liu
- Department of Blood Transfusion, China-Japan Union Hospital of Jilin University, 130033, Changchun, China
| | - Qiang Zhang
- Department of Orthopaedic Surgery, The Second Hospital of Jilin University, 130041, Changchun, China
| | - Hongru Li
- Department of Orthopaedic Surgery, The Second Hospital of Jilin University, 130041, Changchun, China
| | - Xiaoqian Cui
- Department of Emergency and Critical Care, The Second Hospital of Jilin University, 130041, Changchun, PR China
| | - Zhiping Qi
- Department of Orthopaedic Surgery, The Second Hospital of Jilin University, 130041, Changchun, China.
| | - Xiaoyu Yang
- Department of Blood Transfusion, China-Japan Union Hospital of Jilin University, 130033, Changchun, China.
- Department of Orthopaedic Surgery, The Second Hospital of Jilin University, 130041, Changchun, China.
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Luan X, Chen P, Li Y, Yuan X, Miao L, Zhang P, Cao Q, Song X, Di G. TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway. Stem Cell Res Ther 2023; 14:100. [PMID: 37095581 PMCID: PMC10127380 DOI: 10.1186/s13287-023-03342-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/14/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. METHODS In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. RESULTS TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. CONCLUSION In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.
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Affiliation(s)
- Xiaoyu Luan
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Peng Chen
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
- Institute of Stem Cell and Regenerative Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yaxin Li
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Xinying Yuan
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Longyu Miao
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Pengyu Zhang
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Qilong Cao
- Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Xiaomin Song
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Guohu Di
- School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China.
- Institute of Stem Cell and Regenerative Medicine, School of Basic Medicine, Qingdao University, Qingdao, China.
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15
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Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
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Gharbi T, Liu C, Khan H, Zhang Z, Yang GY, Tang Y. Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts. Curr Issues Mol Biol 2023; 45:1982-1997. [PMID: 36975497 PMCID: PMC10047917 DOI: 10.3390/cimb45030127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/21/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Hypoxic preconditioning has been demonstrated to increase the resistance of neural stem cells (NSCs) to hypoxic conditions, as well as to improve their capacity for differentiation and neurogenesis. Extracellular vesicles (EVs) have recently emerged as critical mediators of cell–cell communication, but their role in this hypoxic conditioning is presently unknown. Here, we demonstrated that three hours of hypoxic preconditioning triggers significant neural stem cell EV release. Proteomic profiling of EVs from normal and hypoxic preconditioned neural stem cells identified 20 proteins that were upregulated and 22 proteins that were downregulated after hypoxic preconditioning. We also found an upregulation of some of these proteins by qPCR, thus indicating differences also at the transcript level within the EVs. Among the upregulated proteins are CNP, Cyfip1, CASK, and TUBB5, which are well known to exhibit significant beneficial effects on neural stem cells. Thus, our results not only show a significant difference of protein cargo in EVs consequent to hypoxic exposure, but identify several candidate proteins that might play a pivotal role in the cell-to-cell mediated communication underlying neuronal differentiation, protection, maturation, and survival following exposure to hypoxic conditions.
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17
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Mormone E, Iorio EL, Abate L, Rodolfo C. Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming. Front Neurosci 2023; 17:1073689. [PMID: 36816109 PMCID: PMC9929468 DOI: 10.3389/fnins.2023.1073689] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/13/2023] [Indexed: 02/04/2023] Open
Abstract
Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation's steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency's reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD+-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere's chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.
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Affiliation(s)
- Elisabetta Mormone
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy,*Correspondence: Elisabetta Mormone, ;
| | | | - Lucrezia Abate
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carlo Rodolfo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy,Department of Paediatric Onco-Haematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy,Carlo Rodolfo,
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18
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Barzegari A, Omidi Y, Gueguen V, Meddahi-Pellé A, Letourneur D, Pavon-Djavid G. Nesting and fate of transplanted stem cells in hypoxic/ischemic injured tissues: The role of HIF1α/sirtuins and downstream molecular interactions. Biofactors 2023; 49:6-20. [PMID: 32939878 DOI: 10.1002/biof.1674] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022]
Abstract
The nesting mechanisms and programming for the fate of implanted stem cells in the damaged tissue have been critical issues in designing and achieving cell therapies. The fracture site can induce senescence or apoptosis based on the surrounding harsh conditions, hypoxia, and oxidative stress (OS). Respiration deficiency, disruption in energy metabolism, and consequently OS induction change the biophysical, biochemical, and cellular components of the native tissue. Additionally, the homeostatic molecular players and cell signaling might be changed. Despite all aforementioned issues, in the native stem cell niche, physiological hypoxia is not toxic; rather, it is vitally required for homing, self-renewal, and differentiation. Hence, the key macromolecular players involved in the support of stem cell survival and re-adaptation to a new dysfunctional niche must be understood for managing the cell therapy outcome. Hypoxia-inducible factor 1-alpha is the master transcriptional regulator, involved in the cell response to hypoxia and the adaptation of stem cells to a new niche. This protein is regulated by interaction with sirtuins. Sirtuins are highly conserved NAD+-dependent enzymes that monitor the cellular energy status and modulate gene transcription, genome stability, and energy metabolism in response to environmental signals to modulate the homing and fate of stem cells. Herein, new insights into the nesting of stem cells in hypoxic-ischemic injured tissues were provided and their programming in a new dysfunctional niche along with the involved complex macromolecular players were critically discussed.
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Affiliation(s)
- Abolfazl Barzegari
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida
| | - Virginie Gueguen
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, Villetaneuse, France
| | - Anne Meddahi-Pellé
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, Villetaneuse, France
| | - Didier Letourneur
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, Villetaneuse, France
| | - Graciela Pavon-Djavid
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, Villetaneuse, France
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19
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Andleeb A, Mehmood A, Tariq M, Butt H, Ahmed R, Andleeb A, Ghufran H, Ramzan A, Ejaz A, Malik K, Riazuddin S. Hydrogel patch with pretreated stem cells accelerates wound closure in diabetic rats. BIOMATERIALS ADVANCES 2022; 142:213150. [PMID: 36306556 DOI: 10.1016/j.bioadv.2022.213150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 09/29/2022] [Accepted: 10/07/2022] [Indexed: 06/16/2023]
Abstract
Delay in wound healing is a diabetes mellites resulting disorder causing persistent microbial infections, pain, and poor quality of life. This disorder is treated by several strategies using natural biomaterials, growth factors and stem cells molded into various scaffolds which possess the potential to accelerate the closure of impaired diabetic wounds. In this study, we developed a hydrogel patch using chitosan (CS) and polyethylene glycol (PEG) with laden bone marrow-derived mesenchymal stem cells (BMSCs) that were pretreated with fibroblast growth factor 21 (FGF21). The developed hydrogel patches were characterized by scanning electron microscopy and fourier transform infrared (FTIR) spectroscopy. After studying the swelling behavior, growth factor (FGF21) was used to modulate BMSC in the hyperglycemic environment. Later, FGF21 treated BMSC were embedded in CS/PEG hydrogel patch and their wound closure effect was assessed in diabetic rats. The results showed that CS/PEG hydrogel patches have good biocompatibility and possess efficient BMSC recruiting properties. The application of CS/PEG hydrogel patches accelerated wound closure in diabetic rats as compared to the control groups. However, the use of FGF21 pretreated BMSCs laded CS/PEG hydrogel patches further increased the therapeutic efficacy of wound closure in diabetic rats. This study demonstrated that the application of a hydrogel patch of CS/PEG with FGF21 pretreated BMSCs improves diabetic wound healing, but further studies are needed on larger animals before the use of these dressings in clinical trials.
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Affiliation(s)
- Anisa Andleeb
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan; Department of Biotechnology, Faculty of Natural and Applied Sciences, Mirpur University of Science and Technology, Mirpur 10250, AJK, Pakistan
| | - Azra Mehmood
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Muhammad Tariq
- Department of Biotechnology, Faculty of Natural and Applied Sciences, Mirpur University of Science and Technology, Mirpur 10250, AJK, Pakistan
| | - Hira Butt
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Rashid Ahmed
- Department of Biotechnology, Faculty of Natural and Applied Sciences, Mirpur University of Science and Technology, Mirpur 10250, AJK, Pakistan; Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana Champaign, IL, USA
| | - Aneeta Andleeb
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54590, Pakistan
| | - Hafiz Ghufran
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Amna Ramzan
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Asim Ejaz
- Adipose Stem Cells Center, Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, USA
| | - Kausar Malik
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Sheikh Riazuddin
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan; Jinnah Burn and Reconstructive Surgery Centre, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
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20
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Sart S, Liu C, Zeng EZ, Xu C, Li Y. Downstream bioprocessing of human pluripotent stem cell-derived therapeutics. Eng Life Sci 2022; 22:667-680. [PMID: 36348655 PMCID: PMC9635003 DOI: 10.1002/elsc.202100042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/08/2021] [Accepted: 08/16/2021] [Indexed: 11/30/2022] Open
Abstract
With the advancement in lineage-specific differentiation from human pluripotent stem cells (hPSCs), downstream cell separation has now become a critical step to produce hPSC-derived products. Since differentiation procedures usually result in a heterogeneous cell population, cell separation needs to be performed either to enrich the desired cell population or remove the undesired cell population. This article summarizes recent advances in separation processes for hPSC-derived cells, including the standard separation technologies, such as magnetic-activated cell sorting, as well as the novel separation strategies, such as those based on adhesion strength and metabolic flux. Specifically, the downstream bioprocessing flow and the identification of surface markers for various cell lineages are discussed. While challenges remain for large-scale downstream bioprocessing of hPSC-derived cells, the rational quality-by-design approach should be implemented to enhance the understanding of the relationship between process and the product and to ensure the safety of the produced cells.
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Affiliation(s)
- Sebastien Sart
- Laboratory of Physical Microfluidics and BioengineeringDepartment of Genome and GeneticsInstitut PasteurParisFrance
| | - Chang Liu
- Department of Chemical and Biomedical EngineeringFAMU‐FSU College of EngineeringFlorida State UniversityTallahasseeFLUSA
| | - Eric Z. Zeng
- Department of Chemical and Biomedical EngineeringFAMU‐FSU College of EngineeringFlorida State UniversityTallahasseeFLUSA
| | - Chunhui Xu
- Department of PediatricsEmory University School of Medicine and Children's Healthcare of AtlantaAtlantaGAUSA
| | - Yan Li
- Department of Chemical and Biomedical EngineeringFAMU‐FSU College of EngineeringFlorida State UniversityTallahasseeFLUSA
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21
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Islam MS, Ebrahimi-Barough S, Al Mahtab M, Shirian S, Aghayan HR, Arjmand B, Allahverdi A, Ranjbar FE, Sadeg AB, Ai J. Encapsulation of rat bone marrow-derived mesenchymal stem cells (rBMMSCs) in collagen type I containing platelet-rich plasma for osteoarthritis treatment in rat model. Prog Biomater 2022; 11:385-396. [PMID: 36271317 DOI: 10.1007/s40204-022-00200-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/02/2022] [Indexed: 11/28/2022] Open
Abstract
Osteoarthritis (OA) is the most common form of degenerative joint disease, affecting more than 25% of the adults despite its prevalence in the elderly population. Most of the current therapeutic modalities aim at symptomatic treatment which lingers the disease progression. In recent years, regenerative medicine such as stem cell transplantation and tissue engineering has been suggested as a potential curative intervention for OA. The objective of this current study was to assess the safety and efficacy of an injectable tissue-engineered construct composed of rat bone marrow mesenchymal stem cells (rBMMSCs), platelet-rich plasma (PRP), and collagen type I in rat model of OA. To produce collagen type I, PRP and rBMMSCs, male Wistar rats were ethically euthanized. After isolation, culture, expansion and characterization of rBMMSCs, tissue-engineered construct was formed by a combination of appropriate amount of collagen type I, PRP and rBMMSCs. In vitro studies were conducted to evaluate the effect of PRP on chondrogenic differentiation capacity of encapsulated cells. In the following, the tissue-engineered construct was injected in knee joints of rat models of OA (24 rats in 4 groups: OA, OA + MSC, OA + collagen + MSC + PRP, OA + MSC + collagen). After 6 weeks, the animals were euthanized and knee joint histopathology examinations of knee joint samples were performed to evaluate the effect of each treatment on OA. Tissue-engineered construct was successfully manufactured and in vitro assays demonstrated the relevant chondrogenic genes and proteins expression were higher in PRP group than that of others. Histopathological findings of the knee joint samples showed favorable regenerative effect of rBMMSCs + PRP + collagen group compared to others. We introduced an injectable tissue-engineered product composed of rBMMSCs + PRP + collagen with potential regenerative effect on cartilage that has been damaged by OA.
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Affiliation(s)
- Md Shahidul Islam
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.,Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran
| | - Hamid Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Allahverdi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Esmaeili Ranjbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Amin Bigham Sadeg
- Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.,Shiraz Molecular Pathology Research Center, Dr Daneshbod Path Lab, Shiraz, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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22
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Sarsenova M, Kim Y, Raziyeva K, Kazybay B, Ogay V, Saparov A. Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells. Front Immunol 2022; 13:1010399. [PMID: 36211399 PMCID: PMC9537745 DOI: 10.3389/fimmu.2022.1010399] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/07/2022] [Indexed: 11/19/2022] Open
Abstract
Considering the unique therapeutic potential of mesenchymal stem cells (MSCs), including their immunosuppressive and immunomodulatory properties as well as their ability to improve tissue regeneration, these cells have attracted the attention of scientists and clinicians for the treatment of different inflammatory and immune system mediated disorders. However, various clinical trials using MSCs for the therapeutic purpose are conflicting and differ from the results of promising preclinical studies. This inconsistency is caused by several factors such as poor migration and homing capacities, low survival rate, low level of proliferation and differentiation, and donor-dependent variation of the cells. Enhancement and retention of persistent therapeutic effects of the cells remain a challenge to overcome in MSC-based therapy. In this review, we summarized various approaches to enhance the clinical outcomes of MSC-based therapy as well as revised current and future perspectives for the creation of cellular products with improved potential for diverse clinical applications.
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Affiliation(s)
- Madina Sarsenova
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Bexultan Kazybay
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Vyacheslav Ogay
- Laboratory of Stem Cells, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
- *Correspondence: Arman Saparov,
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23
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Xu H, Takashi E, Liang J, Chen Y, Yuan Y, Fan J. Effect of Heat Shock Preconditioning on Pressure Injury Prevention via Hsp27 Upregulation in Rat Models. Int J Mol Sci 2022; 23:ijms23168955. [PMID: 36012220 PMCID: PMC9408952 DOI: 10.3390/ijms23168955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/23/2022] Open
Abstract
Pressure injury (PI) prevention is a huge industry and involves various interventions. Temperature and moisture are important factors for wound healing; however, the active mechanism by which “moist heat” affects PI prevention has not yet been clarified. Thus, we explored the protective and therapeutic effects of hydrotherapy on PI based on the preconditioning (PC) principle, which might be useful for clinical practice. This study aimed to investigate the preventive mechanisms of heat shock preconditioning on PIs in rat models. The experiment was performed in the basic medical laboratory of Nagano College of Nursing in Japan. Ten rats were divided into two groups, with five rats in each group. Rats in the control group were not bathed. Rats in the preconditioning group (PC group) were bathed with hot tap-water. Bathing was conducted thrice a week. After bathing for 4 weeks, the PI model was constructed on the rats’ dorsal skin. The skin temperature, skin moisture, and area of ulcers were compared between the two groups. In vitro, we investigated the expression of heat shock protein 27 (Hsp27) in 6, 12, and 24 h after the PI model was constructed through Western blot analysis. Ulcers occurred in the control group 24 h after the PI model constructed, wheras the PC group exhibited ulcers after 36 h. The ulcer area was larger in the control group than that in the PC group after 24 h (all p < 0.05). The temperatures of PI wounds in the control group decreased and were lower than those in the PC group after 1, 6, 12, 36, and 48 h (all p < 0.05). However, the skin moisture levels of PI wounds increased in the control group and were higher than those in the PC group at the same time (all p < 0.05). Using Western blot analysis, hydrotherapy preconditioning showed the potential to increase Hsp27 expression after pressure was released (p < 0.05). We determine that heat shock preconditioning had a preventive effect on PIs in rat models, a result that may be associated with their actions in the upregulation of Hsp27.
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Affiliation(s)
- Huiwen Xu
- Division of Basic & Clinical Medicine, Faculty of Nursing, Nagano College of Nursing, Komagane, Nagano 399-4117, Japan
- School of Nursing & Public Health, Yangzhou University, Yangzhou 225000, China
| | - En Takashi
- Division of Basic & Clinical Medicine, Faculty of Nursing, Nagano College of Nursing, Komagane, Nagano 399-4117, Japan
- Correspondence: (E.T.); (J.L.)
| | - Jingyan Liang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, China
- Correspondence: (E.T.); (J.L.)
| | - Yajie Chen
- Department of Molecular Pathology, University of Yamanashi, 1110 Shimokato, Tokyo 409-3898, Japan
| | - Yuan Yuan
- Division of Basic & Clinical Medicine, Faculty of Nursing, Nagano College of Nursing, Komagane, Nagano 399-4117, Japan
- School of Nursing & Public Health, Yangzhou University, Yangzhou 225000, China
| | - Jianglin Fan
- Department of Molecular Pathology, University of Yamanashi, 1110 Shimokato, Tokyo 409-3898, Japan
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24
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Oh S, Kim HM, Batsukh S, Sun HJ, Kim T, Kang D, Son KH, Byun K. High-Intensity Focused Ultrasound Induces Adipogenesis via Control of Cilia in Adipose-Derived Stem Cells in Subcutaneous Adipose Tissue. Int J Mol Sci 2022; 23:ijms23168866. [PMID: 36012125 PMCID: PMC9408610 DOI: 10.3390/ijms23168866] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/30/2022] [Accepted: 08/07/2022] [Indexed: 11/16/2022] Open
Abstract
During skin aging, the volume of subcutaneous adipose tissue (sWAT) and the adipogenesis potential of adipose-derived stem cells (ASCs) decrease. It is known that the shortening of cilia length by pro-inflammatory cytokines is related to the decreased adipogenic differentiation of ASCs via increase in Wnt5a/β-catenin. High-intensity focused ultrasound (HIFU) is known to upregulate heat shock proteins (HSP), which decrease levels of pro-inflammatory cytokines. In this study, we evaluated whether HIFU modulates the cilia of ASCs by upregulating HSP70 and decreasing inflammatory cytokines. HIFU was applied at 0.2 J to rat skin, which was harvested at 1, 3, 7, and 28 days. All results for HIFU-applied animals were compared with control animals that were not treated. HIFU increased expression of HSP70 and decreased expression of NF-κB, IL-6, and TNF-α in sWAT. HIFU decreased the expression of cilia disassembly-related factors (AurA and HDAC9) in ASCs. Furthermore, HIFU increased the expression of cilia assembly-related factors (KIF3A and IFT88), decreased that of WNT5A/β-catenin, and increased that of the adipogenesis markers PPARγ and CEBPα in sWAT. HIFU increased the number of adipocytes in the sWAT and the thickness of sWAT. In conclusion, HIFU could selectively increase sWAT levels by modulating the cilia of ASCs and be used for skin rejuvenation.
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Affiliation(s)
- Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
| | - Hyoung Moon Kim
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
| | - Sosorburam Batsukh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
| | | | | | | | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea
- Correspondence: (K.H.S.); (K.B.); Tel.: +82-32-460-3666 (K.H.S.); +82-32-899-6511 (K.B.)
| | - Kyunghee Byun
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
- Correspondence: (K.H.S.); (K.B.); Tel.: +82-32-460-3666 (K.H.S.); +82-32-899-6511 (K.B.)
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25
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Organ-Specific Differentiation of Human Adipose-Derived Stem Cells in Various Organs of Xenotransplanted Rats: A Pilot Study. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081116. [PMID: 35892918 PMCID: PMC9330795 DOI: 10.3390/life12081116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022]
Abstract
Adipose-derived stem cells (ADSCs) are potential therapeutics considering their self-renewal capacity and ability to differentiate into all somatic cell types in vitro. The ideal ADSC-based therapy is a direct injection into the relevant organs. The objective of this study was to investigate the viability and safety of intra-organ human ADSC (h-ADSC) xenotransplants in vivo. Subcutaneous adipose tissue from the abdominal area of 10 patients was sampled. h-ADSCs were isolated from adipose tissue samples and identified using immunofluorescence antibodies. Multi-differentiation potential assays for adipocytes, osteocytes, and chondrocytes were performed. Cultured h-ADSCs at passage 4 were transplanted into multiple organs of 17 rats, including the skin, subcutaneous layer, liver, kidney, pancreas, and spleen. The h-ADSC-injected organs excised after 100 days were examined, and the survival of h-ADSCs was measured by quantitative real-time polymerase chain reaction (qRT-PCR) using specific human and rat target genes. h-ADSCs confirmed by stem cell phenotyping were induced to differentiate into adipogenic, osteogenic, and chondrogenic lineages in vitro. All rats were healthy and exhibited no side effects during the study; the transplanted h-ADSCs did not cause inflammation and were indiscernible from the native organ cells. The presence of transplanted h-ADSCs was confirmed using qRT-PCR. However, the engrafted survival rates varied as follows: subcutaneous fat (70.6%), followed by the liver (52.9%), pancreas (50.0%), kidney (29.4%), skin (29.4%), and spleen (12.5%). h-ADSCs were successfully transplanted into a rat model, with different survival rates depending on the organ.
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26
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Brancaccio P, Anzilotti S, Cuomo O, Vinciguerra A, Campanile M, Herchuelz A, Amoroso S, Annunziato L, Pignataro G. Preconditioning in hypoxic-ischemic neonate mice triggers Na +-Ca 2+ exchanger-dependent neurogenesis. Cell Death Dis 2022; 8:318. [PMID: 35831286 PMCID: PMC9279453 DOI: 10.1038/s41420-022-01089-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 11/09/2022]
Abstract
To identify alternative interventions in neonatal hypoxic-ischemic encephalopathy, researchers’ attention has been focused to the study of endogenous neuroprotective strategies. Based on the preconditioning concept that a subthreshold insult may protect from a subsequent harmful event, we aimed at identifying a new preconditioning protocol able to enhance Ca2+-dependent neurogenesis in a mouse model of neonatal hypoxia ischemia (HI). To this purpose, we also investigated the role of the preconditioning-linked protein controlling ionic homeostasis, Na+/Ca2+ exchanger (NCX). Hypoxic Preconditioning (HPC) was reproduced by exposing P7 mice to 20’ hypoxia. HI was induced by isolating and cutting the right common carotid artery. A significant reduction in ischemic damage was observed in mice subjected to 20’ hypoxia followed,3 days later, by 60’ HI, thus suggesting that 20’ hypoxia functions as preconditioning stimulus. HPC promoted neuroblasts proliferation in the dentate gyrus mirrored by an increase of NCX1 and NCX3-positive cells and an improvement of behavioral motor performances in HI mice. An attenuation of HPC neuroprotection as well as a reduction in the expression of neurogenesis markers, including p57 and NeuroD1, was observed in preconditioned mice lacking NCX1 or NCX3. In summary, PC in neonatal mice triggers a neurogenic process linked to ionic homeostasis maintenance, regulated by NCX1 and NCX3.
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Affiliation(s)
- P Brancaccio
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II", 80131, Naples, Italy
| | - S Anzilotti
- Department of Science and Technology, University of Sannio, 82100, Benevento, Italy
| | - O Cuomo
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II", 80131, Naples, Italy
| | - A Vinciguerra
- Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", 60126, Ancona, Italy
| | - M Campanile
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II", 80131, Naples, Italy
| | - A Herchuelz
- Laboratoire de Pharmacodynamie et de Therapeutique-Faculté de Médecine Université Libre de Bruxelles, Bruxelles, Belgium
| | - S Amoroso
- Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", 60126, Ancona, Italy
| | - L Annunziato
- IRCCS Synlab SDN S.p.A, via Gianturco 113, 80143, Naples, Italy
| | - G Pignataro
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II", 80131, Naples, Italy.
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27
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Moeinabadi-Bidgoli K, Rezaee M, Rismanchi H, Mohammadi MM, Babajani A. Mesenchymal Stem Cell-Derived Antimicrobial Peptides as Potential Anti-Neoplastic Agents: New Insight into Anticancer Mechanisms of Stem Cells and Exosomes. Front Cell Dev Biol 2022; 10:900418. [PMID: 35874827 PMCID: PMC9298847 DOI: 10.3389/fcell.2022.900418] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs), as adult multipotent cells, possess considerable regenerative and anti-neoplastic effects, from inducing apoptosis in the cancer cells to reducing multidrug resistance that bring them up as an appropriate alternative for cancer treatment. These cells can alter the behavior of cancer cells, the condition of the tumor microenvironment, and the activity of immune cells that result in tumor regression. It has been observed that during inflammatory conditions, a well-known feature of the tumor microenvironment, the MSCs produce and release some molecules called "antimicrobial peptides (AMPs)" with demonstrated anti-neoplastic effects. These peptides have remarkable targeted anticancer effects by attaching to the negatively charged membrane of neoplastic cells, disrupting the membrane, and interfering with intracellular pathways. Therefore, AMPs could be considered as a part of the wide-ranging anti-neoplastic effects of MSCs. This review focuses on the possible anti-neoplastic effects of MSCs-derived AMPs and their mechanisms. It also discusses preconditioning approaches and using exosomes to enhance AMP production and delivery from MSCs to cancer cells. Besides, the clinical administration of MSCs-derived AMPs, along with their challenges in clinical practice, were debated.
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Affiliation(s)
- Kasra Moeinabadi-Bidgoli
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Rismanchi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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28
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Hamrangsekachaee M, Baumann HJ, Pukale DD, Shriver LP, Leipzig ND. Investigating Mechanisms of Subcutaneous Preconditioning Incubation for Neural Stem Cell Embedded Hydrogels. ACS APPLIED BIO MATERIALS 2022; 5:2176-2184. [PMID: 35412793 DOI: 10.1021/acsabm.2c00017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Stem cells are a vital component of regenerative medicine therapies, however, only a fraction of stem cells delivered to the central nervous system following injury survive the inflammatory environment. Previously, we showed that subcutaneous preconditioning of neural stem cell (NSC) embedded hydrogels for 28 days improved spinal cord injury (SCI) functional outcomes over controls. Here, we investigated the mechanism of subcutaneous preconditioning of NSC-embedded hydrogels, with and without the known neurogenic cue, interferon gamma (IFN-γ), for 3, 14, or 28 days to refine and identify subcutaneous preconditioning conditions by measurement of neurogenic markers and cytokines. Studying the preconditioning mechanism, we found that subcutaneous foreign body response (FBR) associated cytokines infiltrated the scaffold in groups with and without NSCs, with time point effects. A pro-inflammatory environment with upregulated interleukin (IL)-6, IL-10, macrophage inflammatory protein (MIP)-1, MIP-2, IFN-γ-inducible protein 10 (IP-10), tumor necrosis factor-α (TNF-α), and IL-12p70 was observed on day 3. By 14 and 28 days, there was an increase in pro-regenerative cytokines (IL-13, IL-4) along with pro-inflammatory markers IL-1β, IP-10, and RANTES (regulated on activation, normal T cell expressed, and secreted) potentially part of the mechanism that had an increased functional outcome in SCI. Coinciding with changes in cytokines, the macrophage population increased over time from 3 to 28 days, whereas neutrophils peaked at 3 days with a significant decrease at later time points. Expression of the neuronal marker βIII tubulin in differentiating NSCs was supported at 3 days in the presence of soluble and immobilized IFN-γ and at 14 days by immobilized IFN-γ only, but it was greatly attenuated in all conditions at 28 days, partially because of dilution via host cell infiltration. We conclude that subcutaneously incubating NSC seeded scaffolds for 3 or 14 days could act as host specific preconditioning through exposure to FBR while retaining βIII tubulin expression of NSCs to further improve the SCI functional outcome observed with 28 day subcutaneous incubation.
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Affiliation(s)
| | - Hannah J Baumann
- Department of Chemistry, The University of Akron, Akron, Ohio 44325, United States
| | - Dipak D Pukale
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Leah P Shriver
- Department of Chemistry, The University of Akron, Akron, Ohio 44325, United States
| | - Nic D Leipzig
- Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States.,Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
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29
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Kim JT, Youn DH, Kim BJ, Rhim JK, Jeon JP. Recent Stem Cell Research on Hemorrhagic Stroke : An Update. J Korean Neurosurg Soc 2022; 65:161-172. [PMID: 35193326 PMCID: PMC8918254 DOI: 10.3340/jkns.2021.0126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/25/2021] [Indexed: 11/27/2022] Open
Abstract
Although technological advances and clinical studies on stem cells have been increasingly reported in stroke, research targeting hemorrhagic stroke is still lacking compared to that targeting ischemic stroke. Studies on hemorrhagic stroke are also being conducted, mainly in the USA and China. However, little research has been conducted in Korea. In reality, stem cell research or treatment is unfamiliar to many domestic neurosurgeons. Nevertheless, given the increased interest in regenerative medicine and the increase of life expectancy, attention should be paid to this topic. In this paper, we summarized pre-clinical rodent studies and clinical trials using stem cells for hemorrhagic stroke. In addition, we discussed results of domestic investigations and future perspectives on stem cell research for a better understanding.
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Affiliation(s)
- Jong-Tae Kim
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Korea
| | - Dong Hyuk Youn
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Korea
| | - Bong Jun Kim
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Korea
| | - Jong Kook Rhim
- Department of Neurosurgery, Jeju National University College of Medicine, Jeju, Korea
| | - Jin Pyeong Jeon
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Korea.,Department of Neurosurgery, Hallym University College of Medicine, Chuncheon, Korea
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30
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Abstract
Cell manipulation in droplets has emerged as one of the great successes of microfluidic technologies, with the development of single-cell screening. However, the droplet format has also served to go beyond single-cell studies, namely by considering the interactions between different cells or between cells and their physical or chemical environment. These studies pose specific challenges linked to the need for long-term culture of adherent cells or the diverse types of measurements associated with complex biological phenomena. Here we review the emergence of droplet microfluidic methods for culturing cells and studying their interactions. We begin by characterizing the quantitative aspects that determine the ability to encapsulate cells, transport molecules, and provide sufficient nutrients within the droplets. This is followed by an evaluation of the biological constraints such as the control of the biochemical environment and promoting the anchorage of adherent cells. This first part ends with a description of measurement methods that have been developed. The second part of the manuscript focuses on applications of these technologies for cancer studies, immunology, and stem cells while paying special attention to the biological relevance of the cellular assays and providing guidelines on improving this relevance.
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Affiliation(s)
- Sébastien Sart
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.,Physical Microfluidics and Bioengineering, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France
| | - Gustave Ronteix
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.,Physical Microfluidics and Bioengineering, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France
| | - Shreyansh Jain
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.,Physical Microfluidics and Bioengineering, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France
| | - Gabriel Amselem
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.,Physical Microfluidics and Bioengineering, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France
| | - Charles N Baroud
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.,Physical Microfluidics and Bioengineering, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France
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31
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Mesenchymal Stromal Cells Preconditioning: A New Strategy to Improve Neuroprotective Properties. Int J Mol Sci 2022; 23:ijms23042088. [PMID: 35216215 PMCID: PMC8878691 DOI: 10.3390/ijms23042088] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 02/01/2023] Open
Abstract
Neurological diseases represent one of the main causes of disability in human life. Consequently, investigating new strategies capable of improving the quality of life in neurological patients is necessary. For decades, researchers have been working to improve the efficacy and safety of mesenchymal stromal cells (MSCs) therapy based on MSCs’ regenerative and immunomodulatory properties and multilinear differentiation potential. Therefore, strategies such as MSCs preconditioning are useful to improve their application to restore damaged neuronal circuits following neurological insults. This review is focused on preconditioning MSCs therapy as a potential application to major neurological diseases. The aim of our work is to summarize both the in vitro and in vivo studies that demonstrate the efficacy of MSC preconditioning on neuronal regeneration and cell survival as a possible application to neurological damage.
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Extended Ischemic Recovery After Implantation of Human Mesenchymal Stem Cell Aggregates Indicated by Sodium MRI at 21.1 T. Transl Stroke Res 2022; 13:543-555. [DOI: 10.1007/s12975-021-00976-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/17/2021] [Accepted: 12/12/2021] [Indexed: 12/19/2022]
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Augmenting Peripheral Nerve Regeneration with Adipose-Derived Stem Cells. Stem Cell Rev Rep 2022; 18:544-558. [PMID: 34417730 PMCID: PMC8858329 DOI: 10.1007/s12015-021-10236-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 02/03/2023]
Abstract
Peripheral nerve injuries (PNIs) are common and debilitating, cause significant health care costs for society, and rely predominately on autografts, which necessitate grafting a nerve section non-locally to repair the nerve injury. One possible approach to improving treatment is bolstering endogenous regenerative mechanisms or bioengineering new nervous tissue in the peripheral nervous system. In this review, we discuss critical-sized nerve gaps and nerve regeneration in rats, and summarize the roles of adipose-derived stem cells (ADSCs) in the treatment of PNIs. Several regenerative treatment modalities for PNI are described: ADSCs differentiating into Schwann cells (SCs), ADSCs secreting growth factors to promote peripheral nerve growth, ADSCs promoting myelination growth, and ADSCs treatments with scaffolds. ADSCs' roles in regenerative treatment and features are compared to mesenchymal stem cells, and the administration routes, cell dosages, and cell fates are discussed. ADSCs secrete neurotrophic factors and exosomes and can differentiate into Schwann cell-like cells (SCLCs) that share features with naturally occurring SCs, including the ability to promote nerve regeneration in the PNS. Future clinical applications are also discussed.
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Choudhery MS. Strategies to improve regenerative potential of mesenchymal stem cells. World J Stem Cells 2021; 13:1845-1862. [PMID: 35069986 PMCID: PMC8727227 DOI: 10.4252/wjsc.v13.i12.1845] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/31/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
In the last few decades, stem cell-based therapies have gained attention worldwide for various diseases and disorders. Adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials. Although MSCs have high self-renewal as well as differentiation potential, such abilities are compromised with "advanced age" and "disease status" of the donor. Similarly, cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells. It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies, however; autologous use of stem cells for such patients (aged and diseased) does not seem to give optimal results due to their compromised potential. In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs. It is therefore essential to improve the regenerative potential of stem cells compromised due to "in vitro expansion", "donor age" and "donor disease status" for their successful autologous use. The current review has been organized to address the age and disease depleted function of resident adult stem cells, and the strategies to improve their potential. To combat the problem of decline in the regenerative potential of cells, this review focuses on the strategies that manipulate the cell environment such as hypoxia, heat shock, caloric restriction and preconditioning with different factors.
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Affiliation(s)
- Mahmood S Choudhery
- Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Punjab, Pakistan
- Department of Genetics and Molecular Biology, University of Health Sciences, Lahore 54600, Punjab, Pakistan.
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35
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Zhang Q, Wan XX, Hu XM, Zhao WJ, Ban XX, Huang YX, Yan WT, Xiong K. Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases. Front Cell Dev Biol 2021; 9:809656. [PMID: 34977045 PMCID: PMC8717932 DOI: 10.3389/fcell.2021.809656] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022] Open
Abstract
Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.
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Affiliation(s)
- Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xin-xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xi-min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wen-juan Zhao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xiao-xia Ban
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan-xia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wei-tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
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Bae JY, Choi SJ, Kim JK. Comparison of mesenchymal stem cell attachment efficiency in acellular neural graft for peripheral nerve regeneration. J Plast Reconstr Aesthet Surg 2021; 75:1674-1681. [PMID: 34955403 DOI: 10.1016/j.bjps.2021.11.098] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 11/13/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023]
Abstract
Decellularized nerve allograft is an alternative to autologous nerve graft for nerve defects but has shown inferior clinical outcomes. Mesenchymal stem cells can play a key role in improving nerve regeneration of decellularized nerve allografts. The purpose of this study was to compare different mesenchymal stem cell seeding methods and to find the most efficient way to attach cells to nerve grafts for peripheral nerve regeneration. Wharton's jelly mesenchymal stem cells were collected from human umbilical cords and were seeded in the acellular nerve graft in five different ways as follows: PBS injection, fibrin glue drop, Matrigel drop, bioreactor, and Matrigel injection. A 6-mm sciatic nerve defect of Sprague-Dawley rats was bridged using mesenchymal stem cells-laden acellular nerve grafts according to the five seeding methods. Two days after implantation, the nerve tissue was biopsied and analyzed by the immunofluorescence staining of nuclei. The number of Wharton's jelly mesenchymal stem cells (+ h Nuclei) was counted in the inside, outside, and the total area of the graft sections under 200X magnification. The highest efficiency of mesenchymal stem cell attachment inside the graft and the highest total number of attached mesenchymal stem cells was observed in the group using Matrigel injection (p < 0.0001). This study showed mesenchymal stem cells can be more effectively attached to decellularized nerve graft using the injection method with Matrigel than other static or dynamic seeding methods in vivo.
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Affiliation(s)
- Joo-Yul Bae
- Department of Orthopedic Surgery, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung-si, Korea
| | | | - Jae Kwang Kim
- Department of Orthopedic Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
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37
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Sumarwoto T, Suroto H, Mahyudin F, Utomo DN, Romaniyanto R, Prijosedjati A, Utomo P, Prakoeswa CRS, Rantam FA, Tinduh D, Notobroto HB, Rhatomy S. Preconditioning of Hypoxic Culture Increases The Therapeutic Potential of Adipose Derived Mesenchymal Stem Cells. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.5870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Various in vitro preconditioning strategies have been implemented to increase the regenerative capacity of MSCs. Among them are modulation of culture atmosphere (hypoxia or anoxia), three-dimensional culture (3D), addition of trophic factors (in the form of growth factors, cytokines or hormones), lipopolysaccharides, and pharmacological agents. Preconditioning mesenchymal stem cells by culturing them in a hypoxic environment, which resembles the natural oxygen environment of the tissues (1% –7%) and not with standard culture conditions (21%), increases the survival of these cells via Hypoxia Inducible Factor-1α (HIF-1a) and via Akt-dependent mechanisms. In addition, the hypoxic precondition stimulates the secretion of pro-angiogenic growth factors, increases the expression of chemokines SDF-1 (stromal cell-derived factor-1) and its receptor CXCR4 (chemokine receptor type 4) - CXCR7 (chemokine receptor type 7) and increases engraftment of stem cell. This review aims to provide an overview of the preconditioned hypoxic treatment to increase the therapeutic potential of adipose-derived mesenchymal stem cells.
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38
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Khawaja H, Fazal N, Yaqub F, Ahmad MR, Hanif M, Yousaf MA, Latief N. Protective and proliferative effect of Aesculus indica extract on stressed human adipose stem cells via downregulation of NF-κB pathway. PLoS One 2021; 16:e0258762. [PMID: 34679084 PMCID: PMC8535185 DOI: 10.1371/journal.pone.0258762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/06/2021] [Indexed: 01/22/2023] Open
Abstract
Inflammatory microenvironment after transplantation affects the proliferation and causes senescence of adipose-derived mesenchymal stem cells (hADMSCs) thus compromising their clinical efficacy. Priming stem cells with herbal extracts is considered very promising to improve their viability in the inflammatory milieu. Aesculus indica (A. indica) is used to treat many inflammatory diseases in Asia for decades. Herein, we explored the protective role of A. indica extract on human adipose-derived Mesenchymal Stem Cells (hADMSCs) against Monosodium Iodoacetate (MIA) induced stress in vitro. A. indica ameliorated the injury as depicted by significantly enhanced proliferation, viability, improved cell migration and superoxide dismutase activity. Furthermore, reduced lactate dehydrogenase activity, reactive oxygen species release, senescent and apoptotic cells were detected in A. indica primed hADMSCs. Downregulation of NF-κB pathway and associated inflammatory genes, NF-κB p65/RelA and p50/NF-κB 1, Interleukin 6 (IL-6), Interleukin 1 (IL-1β), Tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 13 (MMP-13) were observed in A. indica primed hADMSCs as compared to stressed hADMSCs. Complementary to gene expression, A. indica priming reduced the release of transcription factor p65, inhibitory-κB kinase (IKK) α and β, IL-1β and TNF-α proteins expression. Our data elucidates that A. indica extract preconditioning rescued hADMSCs against oxidative stress and improved their therapeutic potential by relieving inflammation through regulation of NF-κB pathway.
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Affiliation(s)
- Hamzah Khawaja
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
- Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, Leipzig University, Leipzig, Germany
| | - Numan Fazal
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Faiza Yaqub
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Rauf Ahmad
- Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Muzaffar Hanif
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Amin Yousaf
- Department of Dermatology, Jinnah Burn & Reconstructive Surgery Centre, Lahore, Pakistan
| | - Noreen Latief
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
- * E-mail: ,
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Pant T, Juric M, Bosnjak ZJ, Dhanasekaran A. Recent Insight on the Non-coding RNAs in Mesenchymal Stem Cell-Derived Exosomes: Regulatory and Therapeutic Role in Regenerative Medicine and Tissue Engineering. Front Cardiovasc Med 2021; 8:737512. [PMID: 34660740 PMCID: PMC8517144 DOI: 10.3389/fcvm.2021.737512] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022] Open
Abstract
Advances in the field of regenerative medicine and tissue engineering over the past few decades have paved the path for cell-free therapy. Numerous stem cell types, including mesenchymal stem cells (MSCs), have been reported to impart therapeutic effects via paracrine secretion of exosomes. The underlying factors and the associated mechanisms contributing to these MSC-derived exosomes' protective effects are, however, poorly understood, limiting their application in the clinic. The exosomes exhibit a diversified repertoire of functional non-coding RNAs (ncRNAs) and have the potential to transfer these biologically active transcripts to the recipient cells, where they are found to modulate a diverse array of functions. Altered expression of the ncRNAs in the exosomes has been linked with the regenerative potential and development of various diseases, including cardiac, neurological, skeletal, and cancer. Also, modulating the expression of ncRNAs in these exosomes has been found to improve their therapeutic impact. Moreover, many of these ncRNAs are expressed explicitly in the MSC-derived exosomes, making them ideal candidates for regenerative medicine, including tissue engineering research. In this review, we detail the recent advances in regenerative medicine and summarize the evidence supporting the altered expression of the ncRNA repertoire specific to MSCs under different degenerative diseases. We also discuss the therapeutic role of these ncRNA for the prevention of these various degenerative diseases and their future in translational medicine.
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Affiliation(s)
- Tarun Pant
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Matea Juric
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Zeljko J. Bosnjak
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States
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40
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Nanda SS, Wang T, Yoon HY, An SSA, Hembram KPSS, Kim K, Yi DK. Enhanced proliferation of rabbit chondrocytes by using a well circulated nanoshock system. Sci Rep 2021; 11:19388. [PMID: 34588578 PMCID: PMC8481538 DOI: 10.1038/s41598-021-98929-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 09/14/2021] [Indexed: 12/27/2022] Open
Abstract
The gold nanorods (GNRs) embedded alginate-chitosan (scaffold), which was designed and fabricated to produce efficient handling of the cell proliferations. Scaffold embedded GNR (SGNR) and NIR (near infrared) irradiations are developing into an interesting medical prognosis tool for rabbit chondrocyte (RC) proliferation. SGNR contained a pattern of uniform pores. Biocompatibility and cellular proliferation achieved by disclosures to NIR irradiations, providing high cell survival. SGNR and NIR irradiations could produce mechanical and biochemical cues for regulating RCs proliferations. To determine the thermal stress, it exposed RCs to 39–42 °C for 0–240 min at the start point of the cell culture cycle. It produced photothermal stress in cellular surrounding (cells located adjacent to and within scaffold) and it deals with the proliferation behavior of RC. All the processes were modeled with experimental criteria and time evolution process. Our system could help the cell proliferation by generating heat for cells. Hence, the present strategy could be implemented for supporting cell therapeutics after transplantation. This implementation would open new design techniques for integrating the interfaces between NIR irradiated and non-irradiated tissues.
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Affiliation(s)
| | - Tuntun Wang
- Department of Chemistry, Myongji University, Yongin, 03674, South Korea
| | - Hong Yeol Yoon
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea
| | - Seong Soo A An
- Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Seongnam, 13120, South Korea
| | - K P S S Hembram
- Optoelectronic Materials and Devices Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea
| | - Kwangmeyung Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea. .,Korea University (KU)-KIST Graduate School of Converging Science and Technology, Seoul, 02841, South Korea.
| | - Dong Kee Yi
- Department of Chemistry, Myongji University, Yongin, 03674, South Korea.
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Shekarchi S, Roushandeh AM, Roudkenar MH, Bahadori MH. Dimethyl fumarate prevents cytotoxicity and apoptosis mediated by oxidative stress in human adipose-derived mesenchymal stem cells. Mol Biol Rep 2021; 48:6375-6385. [PMID: 34426902 DOI: 10.1007/s11033-021-06638-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 08/10/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND The poor survival rate and undesirable homing of transplanted stem cells are the major challenges in stem cell therapy. Addressing the challenge would improve the therapeutic efficacy of these cells. Dimethyl fumarate (DMF) is an anti-inflammatory drug that exerts its effects through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Therefore, its cytoprotective effects on human adipose-derived MSCs (hASCs) against various oxidative stresses have been investigated in this study. METHODS AND RESULTS hASCs were cultured with different concentrations of DMF to evaluate the cytotoxicity of DMF on hASCs using Cell Counting Kit-8 (CCK-8). Besides, the migration ability of the cells after DMF treatment was evaluated using the Transwell method. Furthermore, the expression of HO-1 and NQO-1 was determined using RT-PCR. The cytoprotective effects of DMF on hASCs against the oxidative stress caused by H2O2 and Ultra Violet (UV) were evaluated by assessing cell proliferation and apoptosis. Our results demonstrated that under oxidative stress conditions induced by H2O2 and UV, DMF increased the survival rate and proliferation of the cells and prevented apoptosis. Moreover, the expression of HO-1 and NQO-1 was upregulated in hASCs pretreated with DMF which confirms the activation of the Nrf2 pathway. However, DMF significantly decreased migration in hADSCs (P < 0.0001). CONCLUSION Our findings indicate that DMF enhances the proliferation capability and viability of hASCs and prevents their apoptosis in harsh stressful microenvironments. However, the applicability of DMF as a cytoprotective factor for the augmentation of hASCs requires in-depth preclinical and clinical studies.
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Affiliation(s)
- Shima Shekarchi
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Amaneh Mohammadi Roushandeh
- Burn and Regenerative Medicine Research Center, School of Medicine, Velayat Hospital, Guilan University of Medical Sciences, Rasht, Iran.
| | - Mehryar Habibi Roudkenar
- Burn and Regenerative Medicine Research Center, School of Medicine, Velayat Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Hadi Bahadori
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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Lee CY, Lee S, Jeong S, Lee J, Seo HH, Shin S, Park JH, Song BW, Kim IK, Choi JW, Kim SW, Han G, Lim S, Hwang KC. Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury. Int J Mol Sci 2021; 22:7946. [PMID: 34360711 PMCID: PMC8348609 DOI: 10.3390/ijms22157946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/20/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.
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Affiliation(s)
- Chang Youn Lee
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Seongtae Jeong
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Jiyun Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea; (J.L.); (H.-H.S.)
| | - Hyang-Hee Seo
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea; (J.L.); (H.-H.S.)
| | - Sunhye Shin
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Jun-Hee Park
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Jung-Won Choi
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Gyoonhee Han
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
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Mytsyk M, Cerino G, Reid G, Sole LG, Eckstein FS, Santer D, Marsano A. Long-Term Severe In Vitro Hypoxia Exposure Enhances the Vascularization Potential of Human Adipose Tissue-Derived Stromal Vascular Fraction Cell Engineered Tissues. Int J Mol Sci 2021; 22:ijms22157920. [PMID: 34360685 PMCID: PMC8348696 DOI: 10.3390/ijms22157920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 11/16/2022] Open
Abstract
The therapeutic potential of mesenchymal stromal/stem cells (MSC) for treating cardiac ischemia strongly depends on their paracrine-mediated effects and their engraftment capacity in a hostile environment such as the infarcted myocardium. Adipose tissue-derived stromal vascular fraction (SVF) cells are a mixed population composed mainly of MSC and vascular cells, well known for their high angiogenic potential. A previous study showed that the angiogenic potential of SVF cells was further increased following their in vitro organization in an engineered tissue (patch) after perfusion-based bioreactor culture. This study aimed to investigate the possible changes in the cellular SVF composition, in vivo angiogenic potential, as well as engraftment capability upon in vitro culture in harsh hypoxia conditions. This mimics the possible delayed vascularization of the patch upon implantation in a low perfused myocardium. To this purpose, human SVF cells were seeded on a collagen sponge, cultured for 5 days in a perfusion-based bioreactor under normoxia or hypoxia (21% and <1% of oxygen tension, respectively) and subcutaneously implanted in nude rats for 3 and 28 days. Compared to ambient condition culture, hypoxic tension did not alter the SVF composition in vitro, showing similar numbers of MSC as well as endothelial and mural cells. Nevertheless, in vitro hypoxic culture significantly increased the release of vascular endothelial growth factor (p < 0.001) and the number of proliferating cells (p < 0.00001). Moreover, compared to ambient oxygen culture, exposure to hypoxia significantly enhanced the vessel length density in the engineered tissues following 28 days of implantation. The number of human cells and human proliferating cells in hypoxia-cultured constructs was also significantly increased after 3 and 28 days in vivo, compared to normoxia. These findings show that a possible in vivo delay in oxygen supply might not impair the vascularization potential of SVF- patches, which qualifies them for evaluation in a myocardial ischemia model.
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Affiliation(s)
- Myroslava Mytsyk
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - Giulia Cerino
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - Gregory Reid
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - Laia Gili Sole
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - Friedrich S. Eckstein
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - David Santer
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
| | - Anna Marsano
- Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland; (M.M.); (G.C.); (G.R.); (L.G.S.); (F.S.E.); (D.S.)
- Department of Biomedicine, University Basel, 4031 Basel, Switzerland
- Correspondence: ; Tel.: +41-61-265-29-79
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Photo-Polymerization Damage Protection by Hydrogen Sulfide Donors for 3D-Cell Culture Systems Optimization. Int J Mol Sci 2021; 22:ijms22116095. [PMID: 34198821 PMCID: PMC8201135 DOI: 10.3390/ijms22116095] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 01/04/2023] Open
Abstract
Photo-polymerized hydrogels are ideally suited for stem-cell based tissue regeneration and three dimensional (3D) bioprinting because they can be highly biocompatible, injectable, easy to use, and their mechanical and physical properties can be controlled. However, photo-polymerization involves the use of potentially toxic photo-initiators, exposure to ultraviolet light radiation, formation of free radicals that trigger the cross-linking reaction, and other events whose effects on cells are not yet fully understood. The purpose of this study was to examine the effects of hydrogen sulfide (H2S) in mitigating cellular toxicity of photo-polymerization caused to resident cells during the process of hydrogel formation. H2S, which is the latest discovered member of the gasotransmitter family of gaseous signalling molecules, has a number of established beneficial properties, including cell protection from oxidative damage both directly (by acting as a scavenger molecule) and indirectly (by inducing the expression of anti-oxidant proteins in the cell). Cells were exposed to slow release H2S treatment using pre-conditioning with glutathione-conjugated-garlic extract in order to mitigate toxicity during the photo-polymerization process of hydrogel formation. The protective effects of the H2S treatment were evaluated in both an enzymatic model and a 3D cell culture system using cell viability as a quantitative indicator. The protective effect of H2S treatment of cells is a promising approach to enhance cell survival in tissue engineering applications requiring photo-polymerized hydrogel scaffolds.
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Lv H, Yuan X, Zhang J, Lu T, Yao J, Zheng J, Cai J, Xiao J, Chen H, Xie S, Ruan Y, An Y, Sui X, Yi H. Heat shock preconditioning mesenchymal stem cells attenuate acute lung injury via reducing NLRP3 inflammasome activation in macrophages. Stem Cell Res Ther 2021; 12:290. [PMID: 34001255 PMCID: PMC8127288 DOI: 10.1186/s13287-021-02328-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Acute lung injury (ALI) remains a common cause of morbidity and mortality worldwide, and to date, there is no effective treatment for ALI. Previous studies have revealed that topical administration of mesenchymal stem cells (MSCs) can attenuate the pathological changes in experimental acute lung injury. Heat shock (HS) pretreatment has been identified as a method to enhance the survival and function of cells. The present study aimed to assess whether HS-pretreated MSCs could enhance immunomodulation and recovery from ALI. MATERIALS AND METHODS HS pretreatment was performed at 42 °C for 1 h, and changes in biological characteristics and secretion functions were detected. In an in vivo mouse model of ALI, we intranasally administered pretreated umbilical cord-derived MSCs (UC-MSCs), confirmed their therapeutic effects, and detected the phenotypes of the macrophages in bronchoalveolar lavage fluid (BALF). To elucidate the underlying mechanisms, we cocultured pretreated UC-MSCs with macrophages in vitro, and the expression levels of inflammasome-related proteins in the macrophages were assessed. RESULTS The data showed that UC-MSCs did not exhibit significant changes in viability or biological characteristics after HS pretreatment. The administration of HS-pretreated UC-MSCs to the ALI model improved the pathological changes and lung damage-related indexes, reduced the proinflammatory cytokine levels, and modulated the M1/M2 macrophage balance. Mechanistically, both the in vivo and in vitro studies demonstrated that HS pretreatment enhanced the protein level of HSP70 in UC-MSCs, which negatively modulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in alveolar macrophages. These effects were partially reversed by knocking down HSP70 expression. CONCLUSION HS pretreatment can enhance the beneficial effects of UC-MSCs in inhibiting NLRP3 inflammasome activation in macrophages during ALI. The mechanism may be related to the upregulated expression of HSP70.
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Affiliation(s)
- Haijin Lv
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaofeng Yuan
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of General Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiebin Zhang
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Tongyu Lu
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jia Yao
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jun Zheng
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jianye Cai
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiaqi Xiao
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Haitian Chen
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shujuan Xie
- Vaccine Research Institute of Sun Yat-sen University, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Ruan
- Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuling An
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Xin Sui
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Huimin Yi
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
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Extracellular vesicles isolated from mesenchymal stromal cells primed with neurotrophic factors and signaling modifiers as potential therapeutics for neurodegenerative diseases. Curr Res Transl Med 2021; 69:103286. [DOI: 10.1016/j.retram.2021.103286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022]
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Chang C, Yan J, Yao Z, Zhang C, Li X, Mao H. Effects of Mesenchymal Stem Cell-Derived Paracrine Signals and Their Delivery Strategies. Adv Healthc Mater 2021; 10:e2001689. [PMID: 33433956 PMCID: PMC7995150 DOI: 10.1002/adhm.202001689] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/13/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) have been widely studied as a versatile cell source for tissue regeneration and remodeling due to their potent bioactivity, which includes modulation of inflammation response, macrophage polarization toward proregenerative lineage, promotion of angiogenesis, and reduction in fibrosis. This review focuses on profiling the effects of paracrine signals of MSCs, commonly referred to as the secretome, and highlighting the various engineering approaches to tune the MSC secretome. Recent advances in biomaterials‐based therapeutic strategies for delivery of MSCs and MSC‐derived secretome in the form of extracellular vesicles are discussed, along with their advantages and challenges.
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Affiliation(s)
- Calvin Chang
- Department of Biomedical Engineering, School of Medicine Johns Hopkins University Baltimore MD 21205 USA
- Translational Tissue Engineering Center Johns Hopkins School of Medicine Baltimore MD 21287 USA
- Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA
| | - Jerry Yan
- Department of Biomedical Engineering, School of Medicine Johns Hopkins University Baltimore MD 21205 USA
- Translational Tissue Engineering Center Johns Hopkins School of Medicine Baltimore MD 21287 USA
- Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA
| | - Zhicheng Yao
- Translational Tissue Engineering Center Johns Hopkins School of Medicine Baltimore MD 21287 USA
- Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA
- Department of Materials Science and Engineering, Whiting School of Engineering Johns Hopkins University Baltimore MD 21218 USA
| | - Chi Zhang
- Translational Tissue Engineering Center Johns Hopkins School of Medicine Baltimore MD 21287 USA
- Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA
- Department of Materials Science and Engineering, Whiting School of Engineering Johns Hopkins University Baltimore MD 21218 USA
| | - Xiaowei Li
- Mary and Dick Holland Regenerative Medicine Program and Department of Neurological Sciences University of Nebraska Medical Center Omaha NE 68198 USA
| | - Hai‐Quan Mao
- Department of Biomedical Engineering, School of Medicine Johns Hopkins University Baltimore MD 21205 USA
- Translational Tissue Engineering Center Johns Hopkins School of Medicine Baltimore MD 21287 USA
- Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA
- Department of Materials Science and Engineering, Whiting School of Engineering Johns Hopkins University Baltimore MD 21218 USA
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Yadav M, Kumari P, Yadav V, Kumar S. Pharmacological preconditioning with phosphodiestrase inhibitor: an answer to stem cell survival against ischemic injury through JAK/STAT signaling. Heart Fail Rev 2021; 25:355-366. [PMID: 31309353 DOI: 10.1007/s10741-019-09822-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Stem cell transplantation in regenerative medicine has been widely used in various disorders including cardiovascular diseases (CVD) and emerging next-generation therapy. However, transplanted stem cell encountered ischemia/reperfusion (IR) injury which is a major challenge for stem cell survival. During the acute phase after myocardial infarction (MI) cytokine-rich hostile microenvironment, extensive immune cell infiltration and lack of oxygen have been a bottleneck in cell-based therapy. During prolonged ischemia, intracellular pH and ATP level decrease results in anaerobic metabolism and lactate accumulation. Consequentially, ATPase-dependent ion transport becomes dysfunctional, contributing to calcium overload and cell death by apoptosis and necrosis. Although O2 level revitalizes upon reperfusion, a surge in the generation of reactive oxygen species (ROS) occurs with neutrophil infiltration in ischemic tissues further aggravating the injury. Ischemic preconditioning (IPC) of stem cells with a repeated short cycle of IR results in the release of chemical signals such as NO, ROS, and adenosine which triggers a cascade of signaling events that activates protein kinase C (PKC), Src protein tyrosine kinases, and nuclear factor κB (NF-κB) and subsequently increased synthesis of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), Heme oxygenase-1 [HO-1], aldose reductase, Mn superoxide dismutase, and anti-apoptotic genes (Mcl-1, BCl-xL, c-FLIPL, c-FLIPS). Pharmacological preconditioning uses a phosphodiestrase inhibitor, another mode of protecting stem cell or heart per se from impending ischemic injury in two phases. During the early phase of cardioprotection (2 h), PC leads to increased expression of survival factors like BCl2/Bax ratio while late phase (24 h) showed activation of the JAK/STAT survival pathway. Phosphorylation of STAT3 at two crucial residues, Tyr-705 and Ser-727, allows its entry inside the nucleus and upregulates the expression of protein kinase G-1 (PKG1) which evokes cardioprotective signaling. To confirm, heart-specific conditional STAT3 knockout mice undergone IR surgery, abolishing late-phase cardioprotective effects.
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Affiliation(s)
- Manju Yadav
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, India
| | - Pooja Kumari
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, India
| | - Varsha Yadav
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, India
| | - Sanjay Kumar
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, India.
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Bld 20, Orlando, FL, 32816, USA.
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Wang MY, Wang YX, Li-Ling J, Xie HQ. Adult Stem Cell Therapy for Premature Ovarian Failure: From Bench to Bedside. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:63-78. [PMID: 33427039 DOI: 10.1089/ten.teb.2020.0205] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Premature ovarian failure (POF) is a devastating condition for women of childbearing age with serious health consequences, including distress, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and increased mortality. In addition to the mainstay estrogen therapy, stem cell therapy has been tested as the result of rapid progress in cell biology and reprogramming research. We hereby provide a review for the latest research and issues related with stem cell-based therapy for POF, and provide a commentary on various methods for enhancing its effect. Large amount of animal studies have demonstrated an extensive benefit of stem cells for failed ovarian recovering. As shown by such studies, stem cell therapy can result in recovery of hormonal levels, follicular activation, ovarian angiogenesis, and functional restoration. Meanwhile, a study of molecular pathways revealed that the function of stem cells mainly depends on their paracrine actions, which can produce multiple factors for the promotion of ovarian angiogenesis and regulation of cellular functions. Nevertheless, studies using disease models also revealed certain drawbacks. Clinical trials have shown that menstrual cycle and even pregnancy may occur in POF patients following transplantation of stem cells, although the limitations, including inadequate number of cases and space for the improvement of transplantation methodology. Only with its safety and effect get substantial improvement through laboratory experiments and clinical trials, can stem cell therapy really bring benefits to more patients. Additionally, effective pretreatment and appropriate transplantation methods for stem cells are also required. Taken together, stem cell therapy has shown a great potential for the reversal of POF and is stepping from bench to bedside. Impact statement Premature ovarian failure (POF) is a devastating condition with serious clinical consequences. The purpose of this review was to summarize the current status of stem cell therapy for POF. Considering the diversity of cell types and functions, a rigorous review is required for the guidance for further research into this field. Meanwhile, the challenges and prospect for clinical application of stem cell treatment, methodological improvements, and innovations are addressed.
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Affiliation(s)
- Ming-Yao Wang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yi-Xuan Wang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Jesse Li-Ling
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
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Mesenchymal Stem Cells Pretreatment With Stromal-Derived Factor-1 Alpha Augments Cardiac Function and Angiogenesis in Infarcted Myocardium. Am J Med Sci 2021; 361:765-775. [PMID: 33582157 DOI: 10.1016/j.amjms.2021.01.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 12/15/2020] [Accepted: 01/26/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI). METHODS The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation. RESULTS SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240MSC, SDF1αMSC, and VEGF-A165MSC in comparison to the control group. CONCLUSIONS These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.
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